Abstract
The effect of the C3435T mutation at exon 26 of the MDR1 gene on the expression levels of MDR1 messenger ribonucleic acid (mRNA) was evaluated by means of real-time polymerase chain reaction in 51 biopsy specimens of duodenum obtained from 13 healthy Japanese subjects. The mRNA levels of MDR1 were 0.38 +/- 0.15, 0.56 +/- 0.14, and 1.13 +/- 0.42 (mean value +/- SE) in the subjects with the homozygote of wild-type allele (C/C), compound heterozygote with mutant T allele (C/T), and the homozygote of the mutant allele (T/T), respectively, reasonably explaining the lower digoxin serum concentration after administration of a single oral dose to subjects harboring a mutant T allele. Good correlation (r =.797; P <.01) was observed between the mRNA concentrations of MDR1 and CYP3A4 in the individual biopsy specimens. This finding suggested a lower plasma concentration of the substrates for CYP3A4 in subjects harboring the C3435T mutation of the MDR1 gene.
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / biosynthesis
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
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Adult
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Alleles
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Cytochrome P-450 CYP3A
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Cytochrome P-450 Enzyme System / biosynthesis
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Cytochrome P-450 Enzyme System / genetics
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Cytosine / metabolism
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DNA-Binding Proteins / biosynthesis
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DNA-Binding Proteins / genetics
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Digoxin / blood
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Duodenum / cytology
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Duodenum / enzymology
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Duodenum / metabolism*
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Enterocytes / enzymology
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Enterocytes / metabolism*
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Enzyme Inhibitors / blood
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Exons / genetics*
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Gene Expression Regulation / genetics*
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Genes, MDR / genetics*
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Humans
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Japan
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Male
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Mitochondrial Proteins*
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Mixed Function Oxygenases / biosynthesis
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Mixed Function Oxygenases / genetics
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Multidrug Resistance-Associated Proteins*
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MutS Homolog 3 Protein
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Mutation / genetics*
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RNA, Messenger / biosynthesis*
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RNA, Messenger / genetics
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Ribosomal Proteins / biosynthesis
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Ribosomal Proteins / genetics
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Saccharomyces cerevisiae Proteins*
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Thymine / metabolism
Substances
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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DNA-Binding Proteins
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Enzyme Inhibitors
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MRP2 protein, S cerevisiae
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MSH3 protein, human
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Mitochondrial Proteins
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Multidrug Resistance-Associated Proteins
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MutS Homolog 3 Protein
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RNA, Messenger
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Ribosomal Proteins
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Saccharomyces cerevisiae Proteins
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Digoxin
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Cytosine
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Cytochrome P-450 Enzyme System
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Mixed Function Oxygenases
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CYP3A protein, human
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Cytochrome P-450 CYP3A
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CYP3A4 protein, human
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Thymine
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multidrug resistance-associated protein 1